Journal Article

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Morris, Andrew J., Deng, Jing, Chun, Jerold, Kelly, Elizabeth A. B., Park, Gye Young, Fu, Panfeng, Aidinis, Vassilis, Karpurapu, Manjula, Ackerman, Steven J., Jarjour, Nizar N., Christman, John W., Nyenhuis, Sharmilee, Corbridge, Susan J., Chung, Sangwoon, Xiao, Lei, Ranjan, Ravi, Jaffe, H. Ari, Lee, Yong Gyu, Prestwich, Glenn D., Kaffe, Eleanna, Li, Yongchao, Ninou, Ioanna, Gorshkova, Irina A., Smyth, Susan S., Du, Jian, Natarajan, Viswanathan, Berdyshev, Evgeny

2013

Overview

Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis. To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.

• Publisher: American Thoracic Society
• Subject: Allergens / Allergens - pharmacology / Allergies / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Asthma / Asthma - chemically induced / Asthma - etiology / Asthma - physiopathology / Biological and medical sciences / Bronchoalveolar Lavage Fluid - chemistry / Bronchoscopy / Chronic obstructive pulmonary disease, asthma / Cytokines / Disease Models, Animal / Drug dosages / Enzymes / FDA approval / Humans / Inflammation / Inflammation - etiology / Inflammation - physiopathology / Intensive care medicine / Lavage / Lipids / Lysophospholipids - physiology / Male / Medical sciences / Mice / Mice, Transgenic / Ostomy / Pathogenesis / Phosphoric Diester Hydrolases - analysis / Phosphoric Diester Hydrolases - physiology / Pneumology / Signal Transduction - physiology / Skin / Smooth muscle / Tracheotomy